Ulcerative colitis (UC) is a chronic tissue-destructive disease in which cellular inflammation and inflammatory cytokines ultimately lead to damage of the colonic mucosa. There is no effective cure, and while standard therapies can ameliorate symptoms in some patients, they are not effective in a significant number of patients and can also cause severe side effects. Consequently, new therapeutic approaches are needed to inhibit the inappropriate and exaggerated inflammatory response in UC patients. The new therapeutic target that this application will develop is based on the recent elucidation of the "inflammatory reflux" in which the nervous system through the vagus nerve regulates immune responses by release of acetylcholine which binds to macrophage 17 nicotinic acetylcholine receptors (nAChR) resulting in inhibition of inflammatory cytokine production. The results of Phase I studies demonstrated proof of principle that the17 nicotinic acetylcholine receptor agonist (GTS-21) ameliorates disease symptoms and tissue damage in two mouse models of UC. The goal of this Phase II proposal is to further advance preclinical development of GTS-21. The drug will be evaluated in vivo for its ability to ameliorate development of disease symptoms and colon pathological changes in two models of murine colitis, which resemble human UC. Drugs will be tested alone and combined with conventional UC therapies at either the initiation of colitis or after the development of symptoms. Drug efficacy will be monitored by disease symptoms, histopathology of the colon, and production of inflammatory mediators. We will also prepare and test a formulation of GTS-21 designed for selective delivery to the colon after oral administration. These studies will provide the groundwork for preparation of an IND and future Phase 2 clinical trials. Because GTS-21 will inhibit production of multiple inflammatory cytokines (as shown in Phase I studies) known to be responsible, at least in part, for damage to colonic mucosa, this therapeutic approach should be more effective than other biological therapies that target only one cytokine. Ultimately this work will develop a new therapeutic option for UC patients that is based on a novel anti-inflammatory pathway. GTS-21 may be superior to current treatments and offer a new option for patients unresponsive to conventional therapies. PUBLIC HEALTH RELEVANCE: This project will develop a new drug that will suppress production of multiple inflammatory cytokines for the therapy of patients with ulcerative colitis. It has the potential to benefit patients unresponsive to conventional therapies.